INHIBITORS OF RORgamma

ABSTRACT

The present disclosure relates to processes for the production of salts and crystalline forms of a compound having the formula.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Application No. 62/536,114, filed Jul. 24, 2017, the entire contents of which are incorporated herein by reference.

BACKGROUND

Retinoic acid receptor-related orphan receptors (RORs) are a subfamily of transcription factors in the steroid hormone nuclear receptor superfamily (Jetten & Joo (2006) Adv. Dev. Biol. 2006, 16, 313-355). The ROR family consists of ROR alpha (RORα), ROR beta (RORβ) and ROR gamma (RORγ), each encoded by a separate gene (in human: RORA, RORB and RORC, respectively; in mouse: rora, rorb and rorc, respectively). RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal domain, a highly conserved DNA-binding domain (DBD) consisting of two zinc finger motifs, a hinge domain, and a ligand binding domain (LBD). RORγ has two isoforms: RORγ1 and RORγ2 (also known as RORγt). RORγ1 is expressed in a variety of tissues including thymus, muscle, kidney and liver, while RORγt is exclusively expressed in the cells of the immune system. RORγt has a critical role in thymopoiesis and the development of several secondary lymphoid tissues, and is a key regulator of Thl7 cell differentiation (Jetten, 2009, Nucl. Recept. Signal., 7:e003, doi:10.1621/nrs.07003, Epub 2009 Apr. 3).

Thl7 cells are a subset of T helper cells which preferentially produce the pro-inflammatory cytokines IL-17A, IL-17F, IL-21 and IL-22. Thl7 cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSF and CCL20, are associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, allergy and asthma (Maddur et al., 2012, Am. J. Pathol., 181:8-18). They are also important in the pathogenesis of acne (Thiboutot et al., 2014, J. Invest. Dermatol., 134(2):307-10, doi: 10.1038/jid.2013.400; Agak et al., 2014, J. Invest. Dermatol., 134(2):366-73, doi: 10.1038/jid.2013.334, Epub 2013 Aug. 7), inflammation associated with endometriosis (Hirata et al., 2010, Endocrinol., 151:5468-5476; Hirata et al., 2011, Fertil Steril., July; 96(1):113-7, doi: 10.1016/j.fertnstert.2011.04.060, Epub 2011 May 20), and many other conditions such as multiple sclerosis, rheumatoid arthritis, cancer, metabolic syndrome, obesity hepatosteatosis, insulin resistance, and diabetes (Meissburger et al., 2011, EMBO Mol. Med., 3:637-651; Tosolini et al., 2011, Cancer Res., 71:1263-1271, doi: 10.1158/0008-5472.CAN-10-2907, Epub 2011 Feb. 8; Su et al., 2014, Immunol. Res., 58:118-124, doi: 10.1007/s12026-013-8483-y, Epub 2014 Jan. 9; Carmi et al., 2011, J. Immunol., 186:3462-3471, doi: 10.4049/jimmunol.1002901, Epub 2011 Feb. 7; Chen et al., 2013, Histopathology, 63:225-233, doi: 10.1111/his.12156, Epub 2013 Jun. 6).

Compound 1 is an inhibitor of RORγ and has therapeutic properties against a number of RORγ mediated diseases. Compound 1 is exemplified in U.S. Pat. No. 9,266,886 and has the formula:

Despite its potential for commercialization, Compound 1 is susceptible to oxidation, particularly in solution. This makes it difficult to formulate pharmaceutically acceptable salts and polymorphs which are amendable to large scale manufacturing and formulating. Thus, the need to find alternative manufacturing methods for this potent inhibitor remains.

SUMMARY

A two-step method for the preparation of a bis-hydrogen bromide salt form of Compound 1 was identified. This process involved the formation and isolation of a mono-hydrogen bromide salt of Compound 1 by treatment with hydrobromic acid followed by a second independent treatment step with hydrobromic acid to form a bis-hydrogen bromide salt of Compound 1. This method required the use of HBr and MeOH during the final steps of the synthesis. This transformation led to contamination of the product from production of MeBr. This problem has been solved herein by slurrying the product in a mixture of isopropyl acetate and water. Thus, disclosed herein are methods of removing methyl bromide from a composition comprising methyl bromide and crystalline form D bis-hydrogen bromide salt of Compound 1.

Also provided is a one step process for forming a bis-hydrogen bromide salt form of Compound 1. In this aspect, neutralizing the reductive amination reaction mixture, thereby resulting in precipitation, provided Compound 1 as a free base in high purity and good yield, particularly on a larger scale. For example, reactions were effective at >3 kg scale with 98% yield and in >99 area % purity. See e.g., the Exemplification section. From this, treatment with a sufficient amount of hydrobromic acid afforded the desired bis-hydrogen bromide salt without the need to use MeOH. While no detectable contamination from MeBr was observed, this process led to the formation of a mixture of crystalline forms: Form E, Form F, and Form G. This problem, however, was solved by slurrying the product in a mixture of isopropyl acetate and water to afford a single bis-hydrogen bromide crystal form of Compound 1, i.e., Form D. Thus, in addition to the one-step process, provided herein are methods of converting crystalline Forms E, F and G of a bis-hydrogen bromide salt of Compound 1 to Form D crystalline bis-hydrogen bromide salt of Compound 1.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. depicts an X-ray powder diffraction pattern (XRPD) for Form D of Compound 1.

FIG. 2. depicts a Differential Scanning Calorimetry (DSC) spectrum for Form D of Compound 1.

FIG. 3. depicts a thermal gravimetric analysis (TGA) pattern for Form D of Compound 1.

FIG. 4. depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form D of Compound 1.

FIG. 5. depicts an X-ray powder diffraction pattern (XRPD) for Form E of Compound 1.

FIG. 6. depicts a Differential Scanning Calorimetry (DSC) spectrum for Form E of Compound 1.

FIG. 7. depicts a thermal gravimetric analysis (TGA) pattern for Form E of Compound 1.

FIG. 8. depicts an 1H-NMR spectrum for Compound 1 made by conditions described herein.

DETAILED DESCRIPTION

Provided herein are methods of removing methyl bromide from a composition comprising methyl bromide and a bis-hydrogen bromide salt of Compound 1 (e.g., crystalline Form D of the bis-hydrogen bromide salt of Compound 1) comprising i) slurrying the composition in a mixture of isopropyl acetate/water or a mixture of heptane/water; and ii) separating the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water or the mixture of heptane/water.

Also provided herein are methods for preparing a free base form of Compound 1, the method comprising i) reductively aminating an aldehyde compound represented by the following structural formula:

with an amine compound represented by the following structural formula:

wherein the reductive amination is carried out in the presence of ethanol, and in the presence of an imine reducing agent; ii) quenching the reductive amination mixture with acid; iii) neutralizing the resulting solution with base, thereby precipitating the free base form of the compound; and iv) isolating the precipitated free-based form of the compound from the solution. From the free-base, the bis-hydrogen bromide salt can then be prepared directly (i.e., without first isolating the mono-hydrogen bromide salt) by adding sufficient hydrobromic acid to the free-base to form the bis-hydrogen bromide salt in one step.

Further provided herein are methods of converting crystalline Forms E, F and G of a bis-hydrogen bromide salt having the following structural formula:

to crystalline Form D bis-hydrogen bromide salt comprising i) slurrying a composition comprising one or more of crystalline Forms E, F, and G in a mixture of isopropyl acetate/water; and ii) separating the crystalline form D bis-hydrogen bromide salt from the mixture of isopropyl acetate/water.

The bis-hydrogen bromide salts formed from the processes described herein have a purity of >95% such as, e.g., >96%, >97%, >98%, >99%, or 99.5% or greater.

1. Definitions

When used alone, the term “Form D” refers to the crystalline polymorph Form D of Compound 1. The terms “Form D”, “Form D of Compound 1”, and “crystalline Form D of Compound 1” are used interchangeably. Similarly, when used alone, the term “Form E” refers to the crystalline polymorph Form E of Compound 1. The terms “Form E”, “Form E of Compound 1”, and “crystalline Form E of Compound 1” are used interchangeably.

The term “amorphous” means a solid that is present in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.

“Purity” is expressed in terms of percentage and can be calculated by dividing the mass of the mono- and bis-hydrogen bromide salt forms of Compound 1 by the total mass of the sample, and then multiplying this number by 100. This calculation does not account for solvated forms. Thus, 90% pure or has a purity of 90% means that the designated mono- or bis-hydrogen bromide salt form of Compound 1, or designated polymorphic form makes up 90% by weight of the sample. In one aspect, the purity of the salt and crystalline forms described herein are >90%, >95%, >97%, and >99% pure (e.g., >99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, and 99.9%) by weight. In one aspect, the purity of the salt and crystalline forms described herein are >90%, >95%, >97%, and >99% pure (e.g., >99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, and 99.9%) by weight and free from other salt or polymorphic forms.

When purity is defined in terms of area such as >99% area, it will be understood that this refers to the purity of the identified compound as determined by the HPLC peak area percentage.

The 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation. Therefore, the XRPD patterns/assignments recited herein are not to be construed as absolute and can vary ±0.2 degrees.

“Substantially the same XRPD pattern” means that for comparison purposes, at least 90% of the peaks shown are present. It is to be further understood that for comparison purposes some variability in peak intensities from those shown are allowed, such as ±0.2 degrees.

In one aspect, crystalline Form D of Compound 1 as made by the processes described herein is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Θ angles selected from 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°. Alternatively, crystalline Form D of Compound 1 is characterized by x-ray powder diffraction peaks at 2Θ angles 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°. In another alternative, crystalline Form D of Compound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, or at least thirty-six, x-ray powder diffraction peaks at 2Θ angles selected from Table 1. In another alternative, crystalline Form D of compound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, and 22.46°. In another alternative, crystalline Form D of compound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, 22.46°, 20.70°, 21.02°, 21.70°, 24.36°, and 24.58°. In another alternative, crystalline Form D of compound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, 22.46°, 20.70°, 21.02°, 21.70°, 24.36°, 24.58°, 25.66°, 25.82°, 26.51°, 26.82°, 29.68°, and 33.70°. In another alternative, crystalline Form D of Compound 1 is characterized by x-ray powder diffraction peaks in Table 1. In another aspect, crystalline Form D of Compound 1 has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 1. In another aspect, crystalline Form D of Compound 1 has a DSC pattern that is substantially the same DSC pattern shown in FIG. 2. In another aspect, crystalline Form D of Compound 1 has a TGA pattern that is substantially the same TGA pattern shown in FIG. 3. In one aspect, the crystalline Form D of Compound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above. In one aspect, Form D of Compound 1 is a hydrate (e.g., a dihydrate) having one or more of the XRPD peaks defined above. In another aspect, Form D of Compound 1 is a bis-hydrogen bromide salt that is a dihydrate and has one or more of the XRPD peaks defined above.

TABLE 1 Form D 2- Theta d(A) Height I % 7.579 11.655 45 36 9.02 9.7963 64 51.2 13.403 6.6006 15 12 14.24 6.2147 85 68 14.562 6.0778 31 24.8 15.241 5.8087 125 100 15.9 5.5692 103 82.4 16.8 5.2729 22 17.6 17.162 5.1624 44 35.2 17.342 5.1092 26 20.8 18.54 4.7817 55 44 18.818 4.7117 53 42.4 19.279 4.6001 13 10.4 19.643 4.5157 20 16 20.14 4.4054 48 38.4 20.7 4.2873 49 39.2 21.02 4.2229 42 33.6 21.699 4.0921 49 39.2 22.46 3.9553 88 70.4 23.362 3.8045 24 19.2 23.698 3.7513 17 13.6 24.362 3.6505 41 32.8 24.578 3.619 29 23.2 24.799 3.5873 11 8.8 25.237 3.526 35 28 25.406 3.503 18 14.4 25.659 3.4689 42 33.6 25.822 3.4474 59 47.2 26.102 3.411 25 20 26.506 3.36 27 21.6 26.82 3.3213 67 53.6 27.122 3.285 19 15.2 27.562 3.2336 10 8 28.004 3.1835 19 15.2 28.604 3.1182 20 16 29.679 3.0076 35 28 33.701 2.6573 48 38.4

In one aspect, crystalline Form E formed by the one-step process described herein is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 20 angles selected from 4.1, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°. Alternatively, crystalline Form E of Compound 1 is characterized by x-ray powder diffraction peaks at 20 angles 4.1, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°. In another alternative, crystalline Form E of Compound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, or at least thirty-six x-ray powder diffraction peaks at 20 angles selected from Table 2. In another alternative, crystalline Form E of Compound 1 is characterized by x-ray powder diffraction peaks in Table 2. In another aspect, crystalline Form E of Compound 1 has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 5. In another aspect, crystalline Form E of Compound 1 has a DSC pattern that is substantially the same DSC pattern shown in FIG. 6. In another aspect, crystalline Form E of Compound 1 has a TGA pattern that is substantially the same TGA pattern shown in FIG. 7. In one aspect, the crystalline Form E of Compound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above.

TABLE 2 Form E 2- Theta d(A) Height I % 4.1 21.5348 75 41 5.662 15.5969 17 9.3 5.801 15.2235 16 8.7 8.3 10.6434 157 85.8 11.781 7.5054 15 8.2 12.659 6.9866 183 100 14.008 6.3168 13 7.1 14.241 6.214 12 6.6 14.403 6.1446 13 7.1 14.677 6.0305 11 6 15.7 5.6398 16 8.7 16.34 5.4203 5 2.7 16.644 5.3219 26 14.2 16.98 5.2174 84 45.9 17.523 5.0569 12 6.6 18.388 4.8209 10 5.5 19.015 4.6635 9 4.9 19.16 4.6284 6 3.3 19.44 4.5624 5 2.7 20.02 4.4315 7 3.8 20.579 4.3123 17 9.3 21.323 4.1636 40 21.9 21.68 4.0957 30 16.4 21.9 4.0551 16 8.7 22.487 3.9506 10 5.5 22.914 3.8779 10 5.5 23.685 3.7535 11 6 24.18 3.6777 8 4.4 24.419 3.6422 22 12 24.779 3.5901 31 16.9 24.779 3.5901 31 16.9 25.72 3.4609 20 10.9 26.499 3.3608 10 5.5 27.041 3.2947 14 7.7 27.204 3.2753 17 9.3 28.14 3.1685 6 3.3 28.604 3.1181 13 7.1

2. General Preparation Methods

Provided herein are processes for preparing mono- and bis-hydrogen bromide salts of Compound 1. Starting materials and synthetic methods for preparing Compound 1 and precursor materials can be found in e.g., General Procedure B of U.S. Pat. No. 9,266,886, the contents of which are incorporated herein by reference.

A two-step process was initially developed to form the bis-hydrogen bromide salt of Compound 1. See e.g., Scheme 5 in the Exemplification section, a portion of which is depicted here as Scheme 1. This process comprised first forming and isolating a mono-hydrogen bromide salt of Compound 1 followed by conversion of the mono-hydrogen bromide salt to the bis-hydrogen bromide salt of Compound 1.

While this process initially proved useful in forming the desired product, the combination of HBr and MeOH resulted in product contamination, i.e., excess methyl bromide was present in the initially isolated product. It was not until after significant efforts, that slurrying the product in a mixture of isopropyl acetate and water was found to effectively remove the excess methyl bromide. Although a mixture of heptane and water was also found to be effective, the solubility of the bis-hydrogen bromide crystalline Form D salt was greater in the isopropyl acetate/water mixture, and therefore this mixture was chosen for scale up purposes. A schematic representation of this process is shown below as Scheme 2.

Provided herein, therefore is a method of removing methyl bromide from a composition comprising methyl bromide and a bis-hydrogen bromide salt of Compound 1 (e.g., crystalline Form D of the bis-hydrogen bromide salt of Compound 1) comprising i) slurrying the composition in a mixture of isopropyl acetate/water or a mixture of heptane/water; and ii) separating the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water or the mixture of heptane/water.

In one aspect, removing methyl bromide from a composition comprising methyl bromide and a bis-hydrogen bromide salt of Compound 1 comprises slurrying the composition in a mixture of isopropyl acetate comprising 0.25% to 2.5% v/v of water; and ii) separating the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water. In one aspect, the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.

In some aspects, prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, or greater than 60 ppm. For example, the amount of methyl bromide present in the composition may be from 50 ppm to 1000 ppm. The amounts of methyl bromide present in the composition prior to slurrying refers to the amount present in a dried composition, e.g., prior to slurrying the composition is dried (e.g., at approximately 15 to 50° C. such as 20 to 25° C.) under approximately −0.096 MPa vacuum for 20 hours or more. In a further aspect, prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm; and the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.

In some aspects, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm of methyl bromide present. For example, in certain instances, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having is less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present. In one aspect, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having an amount of methyl bromide present that is below the level of detection.

In some aspects, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present, or an amount of methyl bromide that is below the level of detection; and wherein prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm. In some aspects, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present, or an amount of methyl bromide that is below the level of detection; wherein prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm; and wherein the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.

Also provided is a one-step method for preparing bis-hydrogen bromide salt of Compound 1 was also identified. In this instance, it was found that switching the solvent from CH₂Cl₂ to EtOH in the reductive amination reaction followed by neutralizing the reductive amination mixture, and precipitating the resulting free base afforded a highly purified free-base product, or at least in pure enough form such that it could be directly converted to the bis-hydrogen bromide salt without the separate step of isolating the mono-hydrogen bromide salt. This method is depicted in Scheme 6 below, a portion of which is represented here as Scheme 3.

Thus, in one aspect, provided herein are alternative methods for preparing a free base form of Compound 1, the method comprising i) reductively aminating an aldehyde compound represented by the following structural formula:

with an amine compound represented by the following structural formula:

wherein the reductive amination is carried out in the presence of ethanol, and in the presence of an imine reducing agent; ii) quenching the reductive amination mixture with acid; iii) neutralizing the resulting solution with base, thereby precipitating the free base form of the compound; and iv) isolating the precipitated free-based form of the compound from the solution. In one aspect, a solution of the aldehyde compound in isopropyl acetate is added to a slurry of the imine reducing agent in a solution of the trialkyl amine and the amine compound in ethanol. In one aspect, the acid used for quenching is hydrochloric acid. In one aspect, the base used is an aqueous base such as a solution of aqueous sodium hydroxide. In one aspect, the solution is neutralized in step iii) to pH 5 to 7. In one aspect, the amine compound is formed in situ from treating an acid salt form (e.g., a hydrochloric acid salt such as a di-hydrochloric acid salt) of the amine with a tertiary amine base

Again, tertiary amines for performing reductive aminations are known and include, but are not limited to, trialkylamines such as diisopropylethylamine (DIPEA or iPr₂NEt) and trimethylamine (TEA). See e.g., March's Advanced Organic Chemistry, fifth edition, John Wiley & Sons 2001. In one instance, the amine used is DIPEA.

Again, reducing agents for performing reductive aminations are known and include, but are not limited to, sodium triacetoxyborohydride (NaBH(OAc)₃), sodium borohydride (NaBH₄), palladium on carbon with H₂, and platinum on carbon with H₂. See e.g., March's Advanced Organic Chemistry, fifth edition, John Wiley & Sons 2001. In one instance, the reducing agent is NaBH(OAc)₃.

From the free-base, the bis-hydrogen bromide salt can then be prepared directly (i.e., without first isolating the mono-hydrogen bromide salt) by adding sufficient hydrobromic acid to the free-base to form the bis-hydrogen bromide salt. In one aspect, formation of the bis-hydrogen bromide salt from the free-based further comprises the addition of a mixture of isopropanol, MTBE, and acetic acid. In another aspect, formation of the bis-hydrogen bromide salt from the free-based further comprises the addition of a mixture of acetic acid and MEK.

Here, the amount and concentration of hydrobromic acid that is sufficient to form the bis-hydrogen bromide salt can vary, but is typically from 2 to 5 equivalents of, for example, 35% to 55% hydrobromic acid, 37% to 53% hydrobromic acid, or 40% to 48% hydrobromic acid. In one aspect, 40% or 48% hydrobromic acid is used. In one aspect, 2 to 4 equivalents, 2 to 3 equivalents, 2 to 2.5 equivalents or 2.1 equivalents of 40% or 48% hydrobromic acid is used.

Although the need to isolate the mono-hydrogen bromide salt first prior to forming the bis-hydrogen bromide salt was eliminated with this one-step method, and contamination of product from methyl bromide was absent because of the avoidance of MeOH, the initial bis-hydrogen bromide salt formed was determined to be existed as a mixture of crystalline Forms E, F, and G. Forms F and G were not characterized further. To overcome this problem, it was found that slurrying the mixture of crystalline forms in isopropyl acetate/water resulted in the formation of single crystalline Form D bis-hydrogen bromide salt. See e.g., Scheme 4 below.

Thus, in one aspect, provided herein is a method of converting crystalline Forms E, F and G of the bis-hydrogen bromide salt of Compound 1 to crystalline Form D bis-hydrogen bromide salt, comprising i) slurrying a composition comprising one or more of crystalline forms E, F and G in a mixture of isopropyl acetate/water containing between 0.25%-2.5% v/v; and ii) separating (e.g., via filtration) the crystalline form D of the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water.

In one aspect, the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.

In one aspect, the amount of Form E, F, and G present in the composition is greater than 90% by weight, such as greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, or greater than 98%, greater than 99%.

EXEMPLIFICATION

The following non-limiting examples are provided to further illustrate the present disclosure.

Materials/Methods Differential Scanning Calorimetry (DSC)

DSC was performed using a TA Instruments 2920 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into an aluminum Tzero crimped pan (TOC) and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The data acquisition parameters and pan configuration for each thermogram are displayed in the image in the figure. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., (−30)−250−10 means “from −30° C. to 250° C., at 10° C./min”.

Thermal Gravimetric Analysis (TG)

TG analyses were performed using a TA Instruments Q5000 IR thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel™. Each sample was placed in a platinum pan. The sample was hermetically sealed, the lid pierced, then inserted into the TG furnace. The furnace was heated under nitrogen. The data acquisition parameters for each thermogram are displayed in the in the figure. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., 00-350-10 means “from ambient ° C. to 350° C., at 10° C./min”.

X-Ray Powder Diffraction (XRPD)

XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Kα X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample was sandwiched between 3-μm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. The data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence slit (DS) before the mirror.

Formation and Analysis of Salt Forms Two-Step Formation

The two-step formation to arrive at Form D is shown below in Scheme 5. Intermediate 2 was prepared according to general procedure B in U.S. Pat. No. 9,266,886, the contents of which are incorporated herein by reference.

Intermediate 2 is suspended in dichloromethane and the amine liberated by treatment with diisopropylethylamine. The solution is cooled to −50° C. and subsequently treated with NaBH(OAc)₃ and the aldehyde. After the reductive amination reaction is complete, the bis-hydrogen bromide is isolated by the following sequence of operations. The dichloromethane solution of 3 is acidified with acetic acid, treated with active carbon and filtered. The solvent is switched to isopropanol. Addition of 40% aqueous HBr (1.4 equivalents), cooling to 10-15° C., seeding and continued aging affords the mono-HBr salt. This material was isolated by centrifugation and dried at 30-45° C. in vacuum. The mono-HBr salt is then converted to the bis-HBr salt by dissolving the mono salt in methanol, adding 1.1 equiv of 40% aqueous HBr, then seeding, followed by additions of MTBE and water. The bis-HBr salt is isolated by filtration and drying at 30-45° C. in vacuum. The final product is isolated as the bis-hydrogen bromide salt Form D with contamination from MeBr (approximately 40 ppm or more at laboratory scale and approximately 227 ppm or greater on plant production of 100 grams or greater).

After numerous attempts and various conditions, it was found that slurrying the bis-hydrogen bromide salt Form D from isopropyl acetate containing 1% water at room temperature effectively produced bis-hydrogen bromide salt Form D in high purity. A combination of heptane and water also removed the methyl bromide, but this combination was not pursued further. A summary of the experiments leading up to these conclusions is provided below.

Based on previous research, residual MeBr could be removed effectively by re-crystallizing from MeOH/MTBE/H₂O=1.75 V/12 V/0.15 V. However, considering the potential risk which MeOH may react with HBr contained in Compound 1, MTBE was tried as only re-slurry solvent. Two reactions were carried out under different N₂ atmosphere: Stirring at approximately 30 to 35° C. for 96 h, residual MeBr was 65 ppm and 40 ppm respectively. See Table 3. After re-slurry with 20 V of MTBE at approximately 30 to 35° C. for 116 h, residual MeBr in both reactions was decreased to less than 50 ppm.

TABLE 3 Residual Br Scale Conditions MeBr (ppm) content Yield Note 40 g Re-slurry with 164 (48 h) 21.1% 94.1% Residual 20 V MTBE at 65 (96 h) (Corrected MeOH: 0.07% 30~35° C. and stir 34 (114 h) by KF) MTBE: 0.23% with 180 rpm. 17 (140 h) Adjust to 20~25° C. Filter, and dry N₂ balloon always 40 g Re-slurry with 180 (48 h) 21.4% 93.8% Residual 20 V MTBE at 40 (96 h) (Corrected MeOH: 0.12% 30~35° C. and stir 20 (116 h) by KF) MTBE: 0.11% with 180 rpm. N.D (140 h) Adjust to 20~25° C. Filter, and dry. N₂ flow after 48 h

The developed purification process was then executed in pilot plant study but failed as the residual MeBr was 227 ppm (limitation: Residual MeBr <40 ppm). Because of this, other solvents (DCM, IPAc, and n-heptane) were tried. After investigation, it was found that DCM was not a good choice because the crystal form changed, whereas the crystal form remained consistent with Form D after stirring at approximately 20 to 30° C. for 3 days in IPAc or n-heptane. So studies about how to remove residual MeBr were carried out in IPAc and n-heptane. See Table 4. The effect of removing MeBr was no different after stirring for 23 h (n-heptane: 148 ppm; IPAc: 153 ppm). However, since the solubility of the bis-hydrogen bromide salt Form D was slightly higher than that in n-heptane, IPAc was chosen as the re-slurry solvent. NMR data for bis-hydrogen bromide crystalline Form D of Compound 1 is as follows: ¹H NMR (500 MHz, CD₃OD): δ 9.12 (s, 1H), 9.11 (s, 1H), 8.57 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 5.22 (d, J=16 Hz, 1H), 4.89 (d, J=4.0 Hz, 1H), 4.85 (s, 2H), 4.77 (d, J=17.5 Hz, 1H), 3.42 (m, 2H), 3.37 (q, J=7.5 Hz, 2H), 2.54 (m, 1H), 2.17 (m, 1H), 2.04 (m, 5H), 1.45 (m, 2H), 1.33 (d, J=7.0 Hz, 3H), 1.28 (t, J=7.5 Hz, 3H), 1.23 (m, 2H), 1.11 (d, J=6.5 Hz, 3H).

TABLE 4 Residual MeBr Scale Conditions Time Wet cake Dried cake 7 g Re-slurry 7 g with 3 h 117 201 10 V IPAc at 20~25° 6 h 140 216 C. under nitrogen 23 h 121 153 balloon 7 g Re-slurry 7 g with 3 h 120 201 10 V n-heptane at 6 h 115 227 20~25° C. under 23 h 110 148 nitrogen balloon

To study the influence on the amount of water for the IPAc/water mixture, reactions with different content of water in IPAc were carried out (0.25%, 0.5%, 1.0%, 2.0%). It was found water could improve the efficiency of removing MeBr and that best results were obtained when 1.0% water was used (Table 5, Entry 3; residual MeBr was less than 40 ppm after stirred for 6 h). XRPD was consistent.

TABLE 5 Residual Br MeBr (ppm) content Wet Dried corrected Entry Scale Conditions Time cake cake by KF Note 1 10 g Re-slurry 3 h 102 91 20.95% Residual 10 g with 6 h 44 66 KF: 5.5% MeOH: N.D 5 V IPAc 23 h <40 <40 IPAc: 0.025% containing 0.25% water at 20~25° C. with 150 rpm 2 10 g Re-slurry 3 h 87 66 21.88% Residual 10 g of S 6 h <40 51 KF: 5.85% MeOH: N.D with 5 V IPAc 23 h ND ND IPAc: 0.029% containing 0.5% water at 20~25° C. with 150 rpm 3 10 g Re-slurry 3 h <40 42 21.88% Residual 10 g of S 6 h <40 <40 KF: 5.86% MeOH: N.D with 5 V IPAc 23 h ND ND IPAc: 0.045% containing 1% water at 20~25° C. with 150 rpm 4 10 g Re-slurry 3 h 42 64 22.34% Residual 10 g of S 6 h <40 <40 KF: 5.99% MeOH: N.D with 5 V IPAc 23 h 67 ND IPAc: 0.016% containing 2% water at 20~25° C. with 150 rpm

With the excess methyl bromide problem solved, another drawback to the two-step process was solved. That is, the two-step process also employed methylene chloride as the solvent for the reductive amination procedure. On large manufacturing scale, this would require strict controls due to air and water quality regulations. To overcome these obstacles, a one-step approach to obtain the bis-hydrogen bromide salt Form D directly from the free base of Compound 1 was realized.

One-Step Formation

The one-step approach is shown below in Scheme 6. Intermediate 2 was again prepared according to general procedure Bin U.S. Pat. No. 9,266,886.

A typical reaction can proceed as follows. To the 30-gal reactor was added 2 (5.12 kg, 9.2 mol, 1.0 equiv). In a carboy was charged ethanol (27.3 L, 7 vol relative to sodium triacetoxyborohydride (STAB)) and DIPEA (3.57 kg, 27.6 mol, 3 equiv relative to 2). The solution of DIPEA/EtOH was added to the reactor with the 2 with no stirring. A cloud of amine hydrochloride formed in the reactor making it difficult to see the slurry, so the batch was allowed to sit without stirring until this cloud dissipated. After 35 min, the cloud dissipated and the mixture was gently stirred. In an hour, the solids had dissolved. The batch was stirred gently overnight at 10° C. and then the 2 was drained from the reactor into a carboy.

The reactor was charged with STAB (3.91 kg, 18.4 mol, 2 equiv) and pre-made solution of DIPEA (2.383 kg, 18.4 mol, 2 equiv) and ethanol (27.2 L, 7 vol relative to STAB) with the jacket at −5° C. The mixture was allowed to cool to 0° C. over 20 min. The solution of 2 in DIPEA/EtOH was added over 27 min followed by the free aldehyde solution in IPAc over 45 min. The maximum temperature during the aldehyde addition was 3.7° C. The mixture was stirred for 1 h and was sampled for reaction completion.

The reaction was quenched by the addition of 1 N HCl (31.2 L, 8 vol relative to STAB) over 33 min. The temperature rose to 11° C. during this addition. The solids dissolved during this quench and the solution was stirred 1 h. The quenched reaction was transferred to a 100-gal. Pfaudler, glass-lined reactor with the jacket set to 10° C. To the 100-gal reactor was charged 1 N NaOH solution (31.2 L, 8 vol relative to STAB). After this addition, the pH rose from approximately 5 to approximately 6 and solids precipitated. The free base slurry was allowed to stir overnight at approximately 10° C. for convenience. The batch was then transferred to a pressure filter equipped with a tight weave cloth. The initial filtration was performed with occasional stirring and the batch de-liquored in about 4 h. The reactor and filter cake were washed with DI water (2×16 L) and 1:1 ethanol/DI water (16 L). The washes took approximately 30 min each. The wet cake was conditioned for 2 h under 8 psig of nitrogen and then was dried at a jacket temperature 35° C. The drying was monitored by KF analysis. The wet cake contained 21% water and the dried cake before off-loading was 5.4% water. The yield was 4.97 kg (98%). The HPLC analysis of the product was 99.7 area %. The NMR weight assay was 90.8 wt % (FIG. 8) and the final KF analysis was 4.7% water. Residue-on-ignition (ROI) analysis of the free base indicated it had 0.2% residual inorganic material.

The material can then be converted to the bis-hydrogen bromide salt by e.g., contacting the free base (0.8026 g) with acetic acid (2 vol, 1.6052 ml) and stirring the mixture at 250 RPM, heated 30° C. A 48% HBr solution is then added (0.3438 ml, 2.1 equiv) drop wise over 9 min. MEK (4.816 ml, 6 vol) is then added over 50 minutes and the reaction is seeded with bis-hydrogen bromide salt Form D. MEK (8.000 ml, 10 vol) is added at 2 ml slowly added every 5 min. The mixture is then chilled to 5° C. over 1 hour, filtered, rinsed w/MEK (2×3.21 ml), and dried in 40° C. vacuum oven/21 hrs to afford a mixture of bis-hydrogen bromide crystalline salt Forms E, F, and G. This procedure was also completed on a 2.5 kg scale. These forms were not characterized further. It should be noted that a mixture of acetic acid/MEK (or acetic acid/acetone) prevents the product from oiling out as well as the production of MeBr. To obtain a single crystalline form, the mixture of forms were slurried in isopropyl acetate with 1% water which gave the bis-hydrogen bromide salt Form D with 98% yield and in >99 area % purity.

While have described a number of embodiments of this, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this disclosure. Therefore, it will be appreciated that the scope of this disclosure is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. 

1. A method of removing methyl bromide from a composition comprising methyl bromide and crystalline form D bis-hydrogen bromide salt of a compound having the following structural:

comprising: i) slurrying the composition in a mixture of isopropyl acetate/water or a mixture of heptane/water; and ii) separating the crystalline form D bis-hydrogen bromide salt from the mixture of isopropyl acetate/water or the mixture of heptane/water.
 2. The method of claim 1, wherein the composition is slurried in a mixture of isopropyl acetate/water.
 3. The method of claim 1, wherein the composition is slurried in a mixture of isopropyl acetate comprising 0.25% to 2.5% v/v of water.
 4. The method of claim 1, wherein the composition is slurried in a mixture of isopropyl acetate comprising 0.5% to 2.0% v/v of water.
 5. The method of claim 1, wherein the composition is slurried in a mixture of isopropyl acetate comprising 0.9% to 1.1% v/v of water.
 6. The method of claim 1, wherein the composition comprises greater than 45 ppm of methyl bromide prior to slurrying.
 7. The method of claim 1, wherein the crystalline form D bis-hydrogen bromide salt after separation comprises less than 40 ppm of methyl bromide.
 8. The method of claim 1, wherein the crystalline form D bis-hydrogen bromide salt after separation comprises an amount of methyl bromide that is below the level of detection.
 9. The method of claim 1, wherein the crystalline form D bis-hydrogen bromide salt is separated by filtration. 10-14. (canceled)
 15. A method of forming a compound having the Formula:

comprising the steps of i) reductively aminating an aldehyde compound represented by the following structural formula:

with an amine compound represented by the following structural formula:

wherein the reductive amination is carried out in the presence of an imine reducing agent; ii) quenching the reductive amination mixture with acid; iii) neutralizing the resulting solution with base, thereby precipitating the free base form of the compound; and iv) isolating the precipitated free-base form of the compound.
 16. The method of claim 15, further comprising carrying out the reductive amination in ethanol as the solvent.
 17. The method of claim 15, wherein the acid is hydrochloric acid and the base is sodium hydroxide.
 18. The method of claim 15, wherein the imine reducing agent is sodium triacetoxyborohydride.
 19. The method of claim 15, wherein the solution is neutralized in step iii) to pH 5 to
 7. 20. The method of claim 15, wherein the amine compound is formed in situ from treating an acid salt form of the amine with a tertiary amine base.
 21. The method of claim 15, wherein the amine is formed in situ from treating a di-hydrochloric acid salt form of the amine with diisopropylethylamine.
 22. The method of claim 15, further comprising v) adding to the isolated free base, a sufficient amount of hydrobromic acid to form a bis-hydrogen bromide salt having the formula:


23. The method of claim 22, further comprising the addition of isopropanol, MTBE, and acetic acid.
 24. The method of claim 22, wherein said sufficient amount of hydrobromic acid comprises 2 to 3 equivalents of 40% or 48% hydrobromic acid. 